HLA Class I and Class II Conserved Extended Haplotypes and Their Fragments or Blocks in Mexicans: Implications for the Study of Genetic Diversity in Admixed Populations

Major histocompatibility complex (MHC) genes are highly polymorphic and informative in disease association, transplantation, and population genetics studies with particular importance in the understanding of human population diversity and evolution. The aim of this study was to describe the HLA diversity in Mexican admixed individuals. We studied the polymorphism of MHC class I (HLA-A, -B, -C), and class II (HLA-DRB1, -DQB1) genes using high-resolution sequence based typing (SBT) method and we structured the blocks and conserved extended haplotypes (CEHs) in 234 non-related admixed Mexican individuals (468 haplotypes) by a maximum likelihood method. We found that HLA blocks and CEHs are primarily from Amerindian and Caucasian origin, with smaller participation of African and recent Asian ancestry, demonstrating a great diversity of HLA blocks and CEHs in Mexicans from the central area of Mexico. We also analyzed the degree of admixture in this group using short tandem repeats (STRs) and HLA-B that correlated with the frequency of most probable ancestral HLA-C/−B and -DRB1/−DQB1 blocks and CEHs. Our results contribute to the analysis of the diversity and ancestral contribution of HLA class I and HLA class II alleles and haplotypes of Mexican admixed individuals from Mexico City. This work will help as a reference to improve future studies in Mexicans regarding allotransplantation, immune responses and disease associations

Native American ancestry significantly contributes to neuromyelitis optica susceptibility in the admixed Mexican population

Neuromyelitis Optica (NMO) is an autoimmune disease with a higher prevalence in non-European populations. Because the Mexican population resulted from the admixture between mainly Native American and European populations, we used genome-wide microarray, HLA high-resolution typing and AQP4 gene sequencing data to analyze genetic ancestry and to seek genetic variants conferring NMO susceptibility in admixed Mexican patients. A total of 164 Mexican NMO patients and 1,208 controls were included. On average, NMO patients had a higher proportion of Native American ancestry than controls (68.1% vs 58.6%; p = 5 × 10–6). GWAS identified a HLA region associated with NMO, led by rs9272219 (OR = 2.48, P = 8 × 10–10). Class II HLA alleles HLA-DQB1*03:01, -DRB1*08:02, -DRB1*16:02, -DRB1*14:06 and -DQB1*04:02 showed the most significant associations with NMO risk. Local ancestry estimates suggest that all the NMO-associated alleles within the HLA region are of Native American origin. No novel or missense variants in the AQP4 gene were found in Mexican patients with NMO or multiple sclerosis. To our knowledge, this is the first study supporting the notion that Native American ancestry significantly contributes to NMO susceptibility in an admixed population, and is consistent with differences in NMO epidemiology in Mexico and Latin America.Fil: Romero Hidalgo, Sandra. Instituto Nacional de Medicina Genómica; MéxicoFil: Flores Rivera, José. Instituto Nacional de Neurología y Neurocirugía; MéxicoFil: Rivas Alonso, Verónica. Instituto Nacional de Neurología y Neurocirugía; MéxicoFil: Barquera, Rodrigo. Max Planck Institute For The Science Of Human History; Alemania. Instituto Nacional de Antropología e Historia; MéxicoFil: Villarreal Molina, María Teresa. Instituto Nacional de Medicina Genómica; MéxicoFil: Antuna Puente, Bárbara. Instituto Nacional de Medicina Genómica; MéxicoFil: Macias Kauffer, Luis Rodrigo. Universidad Nacional Autónoma de México; MéxicoFil: Villalobos Comparán, Marisela. Instituto Nacional de Medicina Genómica; MéxicoFil: Ortiz Maldonado, Jair. Instituto Nacional de Neurología y Neurocirugía; MéxicoFil: Yu, Neng. American Red Cross; Estados UnidosFil: Lebedeva, Tatiana V.. American Red Cross; Estados UnidosFil: Alosco, Sharon M.. American Red Cross; Estados UnidosFil: García Rodríguez, Juan Daniel. Instituto Nacional de Medicina Genómica; MéxicoFil: González Torres, Carolina. Instituto Nacional de Medicina Genómica; MéxicoFil: Rosas Madrigal, Sandra. Instituto Nacional de Medicina Genómica; MéxicoFil: Ordoñez, Graciela. Neuroimmunología, Instituto Nacional de Neurología y Neurocirugía; MéxicoFil: Guerrero Camacho, Jorge Luis. Instituto Nacional de Neurología y Neurocirugía; MéxicoFil: Treviño Frenk, Irene. American British Cowdray Medical Center; México. Instituto Nacional de la Nutrición Salvador Zubiran; MéxicoFil: Escamilla Tilch, Monica. Instituto Nacional de la Nutrición Salvador Zubiran; MéxicoFil: García Lechuga, Maricela. Instituto Nacional de la Nutrición Salvador Zubiran; MéxicoFil: Tovar Méndez, Víctor Hugo. Instituto Nacional de la Nutrición Salvador Zubiran; MéxicoFil: Pacheco Ubaldo, Hanna. Instituto Nacional de Antropología E Historia. Escuela Nacional de Antropología E Historia; MéxicoFil: Acuña Alonzo, Victor. Instituto Nacional de Antropología E Historia. Escuela Nacional de Antropología E Historia; MéxicoFil: Bortolini, María Cátira. Universidade Federal do Rio Grande do Sul; BrasilFil: Gallo, Carla. Universidad Peruana Cayetano Heredia; PerúFil: Bedoya Berrío, Gabriel. Universidad de Antioquia; ColombiaFil: Rothhammer, Francisco. Universidad de Tarapacá; ChileFil: Gonzalez-Jose, Rolando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Instituto Patagónico de Ciencias Sociales y Humanas; ArgentinaFil: Ruiz Linares, Andrés. Colegio Universitario de Londres; Reino UnidoFil: Canizales Quinteros, Samuel. Universidad Nacional Autónoma de México; MéxicoFil: Yunis, Edmond. Dana Farber Cancer Institute; Estados UnidosFil: Granados, Julio. Instituto Nacional de la Nutrición Salvador Zubiran; MéxicoFil: Corona, Teresa. Instituto Nacional de Neurología y Neurocirugía; Méxic

Effects of hormonal treatment, maxilofacial surgery-orthodontics, traumatism, and malformation on fluctuating asymmetry

ABSTRACT: In this work we test for the putative association between facial fluctuating asymmetry (FFA) and hormone treatments, maxillofacial surgery, orthodontics, injuries, and malformations. A protocol of five photographs and photogrammetric reconstruction was implemented to place thirty-four 3D landmarks in 3162 individuals aged between 18 and 85 years, belonging to the CANDELA initiative. A Procrustes ANOVA test was used to obtain individual facial fluctuating asymmetry scores. One way ANOVA, Welch, and Levene tests were conducted to explore the potential differences between mean and variance of the response variables. Our results indicate that women who received some hormonal treatment showed higher fluctuating facial asymmetry scores in relation to the unaffected group, this being persistent once the effects of heterozygosity (genetic ancestry) and further variables had been statistically controlled. The shape changes corresponding to this association are focused on the chin, jaw, lower lip, prefrontal region, nose, and ears. Previous reports suggested a potential relationship between facial asymmetry and hormone levels, but to the best of our knowledge there are no reports indicating the causation underlying the association detected here. This report is one more evidence of the association between hormone intake and facial asymmetric features in urban admixed Latin American populations.RESUMEN: En este trabajo se evalúa la relación entre la asimetría fluctuante facial (AFF) y los tratamientos hormonales, cirugías maxilofaciales, ortodoncia, traumatismos y malformaciones. En el marco del proyecto CANDELA, se tomaron cinco fotografías faciales de 3162 voluntarios entre los 18 y 85 años. Por fotogrametría se colocaron 34 landmarks o puntos en 3D y mediante el método Procrustes ANOVA se obtuvieron valores individuales de asimetría fluctuante facial. Se realizó una prueba de ANOVA de una vía y la prueba de Welch y Levene para conocer las diferencias entre media y varianza de los valores de asimetría facial y las variables respuesta. También, se caracterizó la variación morfológica del componente asimétrico de la forma facial mediante técnicas multivariadas sobre los grupos que resultaran diferentes significativamente. Las mujeres que reportaron haber recibido algún tipo de tratamiento hormonal mostraron mayores valores de asimetría fluctuante facial respecto al grupo sin tratamiento. Esta asociación se mantuvo una vez removido el efecto de la heterocigosidad (como indicador de la ancestría) y sin interactuar con el resto de covariables incluidas en el análisis. Los cambios morfológicos asociados a este factor se concentran en el mentón, maxilar labio inferior, región perifrontal, región nasal y orejas. Algunos trabajos anteriores dieron cuenta de la posible relación entre la asimetría facial y los niveles de hormonas, pero no hay estudios que sustenten la relación causal o directa entre la asociación aquí planteada. El presente trabajo es una evidencia más de la asociación entre el consumo de hormonas y modificaciones de caracteres faciales en poblaciones urbanas mestizas latinoamericanas

The immunogenetic diversity of the HLA system in Mexico correlates with underlying population genetic structure

We studied HLA class I (HLA-A, -B) and class II (HLA-DRB1, -DQB1) allele groups and alleles by PCR-SSP based typing in a total of 15,318 mixed ancestry Mexicans from all the states of the country divided into 78 sample sets, providing information regarding allelic and haplotypic frequencies and their linkage disequilibrium, as well as admixture estimates and genetic substructure. We identified the presence of 4268 unique HLA extended haplotypes across Mexico and find that the ten most frequent (HF > 1%) HLA haplotypes with significant linkage disequilibrium (Δ’≥0.1) in Mexico (accounting for 20% of the haplotypic diversity of the country) are of primarily Native American ancestry (A*02~B*39~DRB1*04~DQB1*03:02, A*02~B*35~DRB1*08~DQB1*04, A*68~B*39~DRB1*04~DQB1*03:02, A*02~B*35~DRB1*04~DQB1*03:02, A*24~B*39~DRB1*14~DQB1*03:01, A*24~B*35~DRB1*04~DQB1*03:02, A*24~B*39~DRB1*04~DQB1*03:02, A*02~B*40:02~DRB1*04~DQB1*03:02, A*68~B*35~DRB1*04~DQB1*03:02, A*02~B*15:01~DRB1*04~DQB1*03:02). Admixture estimates obtained by a maximum likelihood method using HLA-A/-B/-DRB1 as genetic estimators revealed that the main genetic components in Mexico as a whole are Native American (ranging from 37.8% in the northern part of the country to 81.5% in the southeastern region) and European (ranging from 11.5% in the southeast to 62.6% in northern Mexico). African admixture ranged from 0.0 to 12.7% not following any specific pattern. We were able to detect three major immunogenetic clusters correlating with genetic diversity and differential admixture within Mexico: North, Central and Southeast, which is in accordance with previous reports using genome-wide data. Our findings provide insights into the population immunogenetic substructure of the whole country and add to the knowledge of mixed ancestry Latin American population genetics, important for disease association studies, detection of demographic signatures on population variation and improved allocation of public health resources.Fil: Barquera, Rodrigo. Max Planck Institute For The Science Of Human History; Alemania. Instituto Nacional de Antropología E Historia. Escuela Nacional de Antropología E Historia; MéxicoFil: Hernández Zaragoza, Diana Iraíz. Técnicas Genéticas Aplicadas A la Clínica (tgac); México. Instituto Nacional de Antropología E Historia. Escuela Nacional de Antropología E Historia; MéxicoFil: Bravo Acevedo, Alicia. Instituto Mexicano del Seguro Social; MéxicoFil: Arrieta Bolaños, Esteban. Universitat Essen; AlemaniaFil: Clayton, Stephen. Max Planck Institute For The Science Of Human History; AlemaniaFil: Acuña Alonzo, Víctor. Instituto Nacional de Antropología E Historia, Mexico; MéxicoFil: Martínez Álvarez, Julio César. Instituto Mexicano del Seguro Social; MéxicoFil: López Gil, Concepción. Instituto Mexicano del Seguro Social; MéxicoFil: Adalid Sáinz, Carmen. Instituto Mexicano del Seguro Social; MéxicoFil: Vega Martínez, María del Rosario. Hospital Central Sur de Alta Especialidad; MéxicoFil: Escobedo Ruíz, Araceli. Instituto Mexicano del Seguro Social; MéxicoFil: Juárez Cortés, Eva Dolores. Instituto Mexicano del Seguro Social; MéxicoFil: Immel, Alexander. Max Planck Institute For The Science Of Human History; Alemania. Christian Albrechts Universitat Zu Kiel; AlemaniaFil: Pacheco Ubaldo, Hanna. Instituto Nacional de Antropología E Historia. Escuela Nacional de Antropología E Historia; MéxicoFil: González Medina, Liliana. Instituto Nacional de Antropología E Historia. Escuela Nacional de Antropología E Historia; MéxicoFil: Lona Sánchez, Abraham. Instituto Nacional de Antropología E Historia. Escuela Nacional de Antropología E Historia; MéxicoFil: Lara Riegos, Julio. Universidad Autónoma de Yucatán; MéxicoFil: Sánchez Fernández, María Guadalupe de Jesús. Instituto Mexicano del Seguro Social; MéxicoFil: Díaz López, Rosario. Hospital Central Militar, Mexico City; MéxicoFil: Guizar López, Gregorio Ulises. Hospital Central Militar, Mexico City; MéxicoFil: Medina Escobedo, Carolina Elizabeth. Instituto Mexicano del Seguro Social; MéxicoFil: Arrazola García, María Araceli. Instituto Mexicano del Seguro Social; MéxicoFil: Montiel Hernández, Gustavo Daniel. Instituto Nacional de Antropología E Historia. Escuela Nacional de Antropología E Historia; MéxicoFil: Hernández Hernández, Ofelia. Técnicas Genéticas Aplicadas a la Clínica ; MéxicoFil: Ramos de la Cruz, Flor del Rocío. Instituto Mexicano del Seguro Social; MéxicoFil: Juárez Nicolás, Francisco. Instituto Nacional de Pediatría; MéxicoFil: Pantoja Torres, Jorge Arturo. Instituto Mexicano del Seguro Social; MéxicoFil: Rodríguez Munguía, Tirzo Jesús. Hospital General Norberto Treviño Zapata; MéxicoFil: Juárez Barreto, Vicencio. Hospital Infantil de Mexico Federico Gomez; MéxicoFil: Gonzalez-Jose, Rolando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico. Instituto Patagónico de Ciencias Sociales y Humanas; Argentin

Mendelian Randomization Analysis of the Relationship Between Native American Ancestry and Gallbladder Cancer Risk

Background A strong association between the proportion of Native American ancestry and the risk of gallbladder cancer (GBC) has been reported in observational studies. Chileans show the highest incidence of GBC worldwide, and the Mapuche are the largest Native American people in Chile. We set out to investigate the causal association between Native American Mapuche ancestry and GBC risk, and the possible mediating effects of gallstone disease and body mass index (BMI) on this association. Methods Markers of Mapuche ancestry were selected based on the informativeness for assignment measure and then used as instrumental variables in two-sample mendelian randomization (MR) analyses and complementary sensitivity analyses. Result We found evidence of a causal effect of Mapuche ancestry on GBC risk (inverse variance-weighted (IVW) risk increase of 0.8% for every 1% increase in Mapuche ancestry proportion, 95% CI 0.4% to 1.2%, p = 6.6×10-5). Mapuche ancestry was also causally linked to gallstone disease (IVW risk increase of 3.6% per 1% increase in Mapuche proportion, 95% CI 3.1% to 4.0%, p = 1.0×10-59), suggesting a mediating effect of gallstones in the relationship between Mapuche ancestry and GBC. In contrast, the proportion of Mapuche ancestry showed a negative causal effect on BMI (IVW estimate -0.006 kg/m2 per 1% increase in Mapuche proportion, 95% CI -0.009 to -0.003, p = 4.4×10-5). Conclusions The results presented here may have significant implications for GBC prevention and are important for future admixture mapping studies. Given that the association between Mapuche ancestry and GBC risk previously noted in observational studies appears to be causal, primary and secondary prevention strategies that take into account the individual proportion of Mapuche ancestry could be particularly efficient

Genome-Wide Association Study Identifies a Functional SIDT2 Variant Associated With HDL-C (High-Density Lipoprotein Cholesterol) Levels and Premature Coronary Artery Disease

ObjectiveLow HDL-C (high-density lipoprotein cholesterol) is the most frequent dyslipidemia in Mexicans, but few studies have examined the underlying genetic basis. Our purpose was to identify genetic variants associated with HDL-C levels and cardiovascular risk in the Mexican population.Approach and resultsA genome-wide association studies for HDL-C levels in 2335 Mexicans, identified four loci associated with genome-wide significance: CETP, ABCA1, LIPC, and SIDT2. The SIDT2 missense Val636Ile variant was associated with HDL-C levels and was replicated in 3 independent cohorts (P=5.9×10−18 in the conjoint analysis). The SIDT2/Val636Ile variant is more frequent in Native American and derived populations than in other ethnic groups. This variant was also associated with increased ApoA1 and glycerophospholipid serum levels, decreased LDL-C (low-density lipoprotein cholesterol) and ApoB levels, and a lower risk of premature CAD. Because SIDT2 was previously identified as a protein involved in sterol transport, we tested whether the SIDT2/Ile636 protein affected this function using an in vitro site-directed mutagenesis approach. The SIDT2/Ile636 protein showed increased uptake of the cholesterol analog dehydroergosterol, suggesting this variant affects function. Finally, liver transcriptome data from humans and the Hybrid Mouse Diversity Panel are consistent with the involvement of SIDT2 in lipid and lipoprotein metabolism.ConclusionsThis is the first genome-wide association study for HDL-C levels seeking associations with coronary artery disease in the Mexican population. Our findings provide new insight into the genetic architecture of HDL-C and highlight SIDT2 as a new player in cholesterol and lipoprotein metabolism in humans

A functional ABCA1 gene variant is associated with low HDL-cholesterol levels and shows evidence of positive selection in Native Americans

9 páginas, 5 figuras, 1 tabla.-- Acuña-Alonzo, Víctor et al.It has been suggested that the higher susceptibility of Hispanics to metabolic disease is related to their Native American heritage. A frequent cholesterol transporter ABCA1 (ATP-binding cassette transporter A1) gene variant (R230C, rs9282541) apparently exclusive to Native American individuals was associated with low high-density lipoprotein cholesterol (HDL-C) levels, obesity and type 2 diabetes in Mexican Mestizos. We performed a more extensive analysis of this variant in 4405 Native Americans and 863 individuals from other ethnic groups to investigate genetic evidence of positive selection, to assess its functional effect in vitro and to explore associations with HDL-C levels and other metabolic traits. The C230 allele was found in 29 of 36 Native American groups, but not in European, Asian or African individuals. C230 was observed on a single haplotype, and C230-bearing chromosomes showed longer relative haplotype extension compared with other haplotypes in the Americas. Additionally, single-nucleotide polymorphism data from the Human Genome Diversity Panel Native American populations were enriched in significant integrated haplotype score values in the region upstream of the ABCA1 gene. Cells expressing the C230 allele showed a 27% cholesterol efflux reduction (P< 0.001), confirming this variant has a functional effect in vitro. Moreover, the C230 allele was associated with lower HDL-C levels (P = 1.77 × 10−11) and with higher body mass index (P = 0.0001) in the combined analysis of Native American populations. This is the first report of a common functional variant exclusive to Native American and descent populations, which is a major determinant of HDL-C levels and may have contributed to the adaptive evolution of Native American populations.This research was supported by grant 69856 from the Consejo Nacional de Ciencia y Tecnología (CONACYT) México, and partly supported by grant 660 from the Fundacio´n Mexicana para la Salud-Silanes; by the Intramural Research Program of the National Institute of Digestive and Kidney Diseases (NIDDK), NIH; and by a grant of the Canadian Institutes of Health Research (CIHR). V.A.-A., T.F.-D., M.V.-C. and L.J.-A. were supported by fellowships from CONACYT, México. J.K.K. was supported by fellowships of the Michael Smith Foundation for Health Research (MSFHR) and the CIHR. M.R.H. holds a Canada Research Chair in Human Genetics.Peer reviewe

Cambio cultural, estilo de vida, adiposidad y niveles de glucosa en una comunidad totonaca de la Sierra Norte de Puebla

En el contexto de los estudios sobre los cambios en la alimentacion en las poblaciones indigenas de Mexico se realizo un estudio en una comunidad totonaca de la Sierra Norte de Puebla con dos objetivos: 1) estimar la prevalencia de hiperglucemia y obesidad en la población adulta (N = 229) mediante analisis bioquimicos y mediciones antropometricas y 2) aproximarse a las causas y formas en que ocurrieron los cambios en la alimentacion, actividad fisica y salud que explican el aumento de hiperglucemia y obesidad desde la perspectiva de los propios habitantes de la comunidad. En este estudio encontramos que 19.2 % de la muestra presenta obesidad (IMC ? 30) y 26.3 % trastorno de la glucosa en ayunas (glucosa serica ? 110 mg/dL). Al considerar que estos porcentajes son muy elevados para una comunidad rural, nos enfocamos en realizar un estudio etnografico en el cual se indago sobre los cambios en laalimentacion, actividad fisica, condiciones de vida y salud, y obtuvimos una detallada descripción de la dieta tradicional y actual, la cual aporta una perspectiva general de los elementos de cambio mas relevantes desde el punto de vista de los habitantes de la comunidad. Consideramos como factores cruciales en la modificacion de la dieta y la actividad fisica los cambios ocurridos a raíz de que se desarrollaron las vias de comunicacion, las cuales facilitaron la introduccion de nuevos alimentos que paulatinamente fueron desplazando a los productos locales. Sin embargo, esto no quiere decir que la dieta tradicional haya desaparecido por completo, pues aun se sigue basando en los alimentos cultivados en los huertos familiares, siendo la base principal el maiz producido de manera local

Characterization of complete mitochondrial genomes of indigenous Mayans in Mexico

Background: The authors have previously published the complete mitochondrial genome (mitogenome) sequences of two indigenous Mesoamerican populations, Mazahua (n = 25) and Zapotec (n = 88). Methods: This study determined the complete mitogenome sequences of nine unrelated individuals from the indigenous Maya population living in Mexico. Results: Their mitogenome sequences could be classified into either of the haplogroups A2 and C1. Surprisingly, there were no mitogenome sequences (haplotypes) that the Maya, Mazahua, and Zapotec people share in common. Conclusions: This indicates that no genetic exchange, at least matrilineally, has occurred among them

Historic Treponema pallidum genomes from Colonial Mexico retrieved from archaeological remains.

Treponema pallidum infections occur worldwide causing, among other diseases, syphilis and yaws. In particular sexually transmitted syphilis is regarded as a re-emerging infectious disease with millions of new infections annually. Here we present three historic T. pallidum genomes (two from T. pallidum ssp. pallidum and one from T. pallidum ssp. pertenue) that have been reconstructed from skeletons recovered from the Convent of Santa Isabel in Mexico City, operational between the 17th and 19th century. Our analyses indicate that different T. pallidum subspecies caused similar diagnostic presentations that are normally associated with syphilis in infants, and potential evidence of a congenital infection of T. pallidum ssp. pertenue, the causative agent of yaws. This first reconstruction of T. pallidum genomes from archaeological material opens the possibility of studying its evolutionary history at a resolution previously assumed to be out of reach